Among the millions of patients who receive chemotherapy for cancer, many develop painful peripheral neuropathy. In fact, pain is the principal dose-limiting side effect of chemotherapy, and patients often will receive smaller doses or forego treatment which impacts survival. It is critical to manage this neuropathic pain so that treatment can be optimized. This is a proposal to determine whether cannabinoids may be beneficial for the treatment of chemotherapy-associated pain. Cannabinoid receptors (CB1 and CB2) are located in the periphery, as well as the central nervous system, and modulate nociception. We will investigate whether increased activation of peripheral cannabinoid receptors, or increasing the bioavailability of endogenous cannabinoids (endocannabinoids), will reduce neuropathic pain from chemotherapy. We developed a murine model of neuropathic pain using the chemotherapeutic agent cisplatin, the most widely used chemotherapeutic agent which is often associated with neuropathy. Preliminary data show that mechanical hyperalgesia develops following cisplatin, and cannabinoids given into the hindpaw reduce the hyperalgesia. A multidisciplinary approach employing parallel behavioral, electrophysiological, and cellular studies in mice will be used to investigate changes in endocannabinoid signaling in the periphery that may contribute to cisplatin-evoked hyperalgesia and mechanisms by which cannabinoids may attenuate hyperalgesia. Specifically, we will determine whether injection of cannabinoids or drugs that block degradation of endocannabinoids into the hindpaw attenuate cisplatin-evoked hyperalgesia and sensitization of cutaneous nociceptors. In cellular studies of primary sensory neurons isolated from cisplatin-treated mice, we will determine whether cisplatin alters cannabinoid signaling and receptor expression that may contribute to the hyperalgesia or to the antihyperalgesic effects of cannabinoids. Results from these studies will provide new information on the mechanisms underlying pain from chemotherapy, and will provide a rationale for exploring the use of peripherally-acting cannabinoids in managing pain associated with chemotherapy.